On the flip side, atypical HUS is more frequently seen in adults and is commonly due to mutations involving complement factor H (CFH), I (CFI) and membrane complex protein (MCP). These are glycoproteins synthesized in the liver and play a major role in stabilizing the C3 convertase of the alternate complement pathway. Mutations in the genes that encode these plasma proteins and complement components (C3 and factor B) leads to unregulated activation of the alternate complement pathway, thereby precipitating atypical HUS. Low C3 levels therefore serve as a clue to the presence of atypical HUS in these patients.
Unlike typical HUS, patients with atypical HUS have high (25%) mortality, with progression to ESRD in up to 50-60%. Nate had a nice discussion about the use of Eculizumab (anti complement factor C5) in atypical HUS. Kidney transplantation (see recent review for more information) have variable outcomes in this subgroup, and in fact, live related donor kidney transplantation is contraindicated in patients with CFH and CFI mutations due to increased risk of occurrence of HUS in the donor and 80-90% chance of recurrence in the recipient in first 6 months following transplant.
Due to such varied outcomes, it is essential that the correct cause of HUS is identified at the time of presentation. It should be noted that presence or absence of diarrhea to differentiate these two types is not reliable and up to 20% patients with atypical HUS may have diarrhea as their symptom.Also, not all cases of atypical HUS have a family history of the disease. Correct diagnosis can therefore only be made if evaluation of patients with HUS includes assays for CFH, CFI, MCP, C3 and factor B at the time of diagnosis and prior to initiation of plasma exchange therapy in addition to routinely done tests such as stool studies for EHEC, shigella, campylobacter and salmonella, lupus serologies C3, C4, and ADAMTS 13 activity levels. Accurate identification of the cause of HUS can help the nephrologists in identifying patients who may or may not benefit from kidney transplantation and also for offering other treatment options such as combined liver and kidney transplantation for CFH/CFI mutations with pre operative plasma exchange and isolated kidney transplantation with preoperative plasma exchange for MCP mutations.
So, the next time you are consulted for management of patients with HUS, make sure you get it right…the first time.
Viresh Mohanlal, MD